Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands

Abstract

Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid molecules named specific and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show novel SNIPERs capable of inducing proteasomal degradation of the androgen receptor (AR). Through derivatization of the SNIPER(AR) molecule at the AR ligand and IAP ligand and linker, we developed 42a (SNIPER(AR)-51), which shows effective protein knockdown activity against AR. Consistent with the degradation of the AR protein, 42a inhibits AR-mediated gene expression and proliferation of androgen-dependent prostate cancer cells. In addition, 42a efficiently induces caspase activation and apoptosis in prostate cancer cells, which was not observed in the cells treated with AR antagonists. These results suggest that SNIPER(AR)s could be leads for an anticancer drug against prostate cancers that exhibit AR-dependent proliferation.

Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein

“…Furthermore, the SNIPER(ER)-87 reduced ERα levels in tumor xenografts and suppressed the growth of ERα-positive breast tumors in mice. 28,33) In addition, by derivatization of the IAP ligand molecule, we have developed novel SNIPER(ER) s whose protein degradation and anti-tumor activities are more potent than SNIPER(ER)-87. 33) PROTACs [58][59][60][61] are hybrid molecules that recruit different E3 ubiquitin ligases, such as CRL2 VHL , 35,41,46,47) CRL4 CRBN , 38,39,42,43,45,48,[50][51][52] Mdm2, 36) and CRL3 KEAP1 .…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Targeted protein degradation, using heterobifunctional small molecules (PROTACs) to remove protein targets from within cells, has emerged as a novel strategy for drug development, with the opportunity of providing therapeutic interventions not achievable with existing occupancy‐based enzyme inhibition approaches . Small‐molecular‐weight synthetic PROTACs ( 185‐189 ) have been used to selectively degrade various specific proteins (Figure ), including pirin, sirt2, BET protein, androgen receptor, and BRD4 protein …”

“…3.1 | To design (PROTACs) by exploiting the solvent-exposed region Targeted protein degradation, using heterobifunctional small molecules (PROTACs) to remove protein targets from within cells, has emerged as a novel strategy for drug development, with the opportunity of providing therapeutic interventions not achievable with existing occupancy-based enzyme inhibition approaches. [156][157][158][159][160][161] Small-molecularweight synthetic PROTACs (185)(186)(187)(188)(189) have been used to selectively degrade various specific proteins (Figure 26), including pirin, 162 sirt2, 163 BET protein, 164 androgen receptor, 165 and BRD4 protein. 166 PROTACs consist of a targeting ligand (warhead) for the specific protein to be degraded, an E3 ubiquitin ligase recruitment binder, and a suitable linker connecting the two binders ( Figure 27).…”

Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

“…A recent development is the nongenetic inhibitor of apoptosis protein (IAP)‐dependent protein erasers for AR, SNIPER(AR)s. These hybrid small molecules consist of an AR ligand tethered to the E3 ubiquitin ligase IAP. These compounds degrade AR via UPD and subsequently reduce PCa growth . Similar hybrids and chimeric inhibitors can be developed using other E3 ligases discussed above for a pharmacological treatment.…”

“…These compounds degrade AR via UPD and subsequently reduce PCa growth. 42 Similar hybrids and chimeric inhibitors can be developed using other E3 ligases discussed above for a pharmacological treatment.…”